ArticleCancer immunology research2021
Chronic Adrenergic Stress Contributes to Metabolic Dysfunction and an Exhausted Phenotype in T Cells in the Tumor Microenvironment.
Article in Cancer immunology research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers, 2 of them syntheses that pooled it.
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Who cites it
115 citing papers in PubMed, 2 syntheses or guidelines pooled it, 126 citations in OpenAlex.
- Chronic psychosocial stress: a role in breast cancer etiology?Frontiers in oncology · 2026Pooled it
- The Neuroimmunome of Hepatitis Patients Associates With Disease Severity.Journal of medical virology · 2025Pooled it
- Neuroimmune crosstalk in cancer: emerging immunotherapeutic opportunities.Journal for immunotherapy of cancer · 2026Review
- Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review).Oncology letters · 2026Review
- Chronic stress and myeloid immunosuppression in cancer: A neuroimmune link to behavioral dysfunction.Brain, behavior, & immunity - health · 2026Review
- Neural-tumor interactions: bidirectional regulatory mechanisms and nervous system-targeted tumor therapeutic strategies.Biomarker research · 2026Review
- Heterogeneity in cancer: molecular mechanisms and therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- Neuron-Associated Transcriptional Enrichment Is Associated with Distinct Biological States and Predicts Poor Prognosis in Gastric Cancer.Annals of surgical oncology · 2026Article
- Emotional distress and clinical response to neoadjuvant chemoimmunotherapy in resectable non-small-cell lung cancer: a protocol for the prospective observational NeoFUSE-Lung cohort study.Translational lung cancer research · 2026Article
- Neural regulation of cancer: from microenvironmental hijacking to systemic circuit co-option.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Targeting β-Adrenergic Signaling in Colorectal Cancer: Molecular Mechanisms and Therapeutic Potential of β-Blockers.Cancers · 2026Review
- Electroacupuncture enhances CD8+ T cells recruitmentmodulating sympathetic nervous system to suppress tumor growth in mice bearing triple-negative breast cancer.Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan · 2026Article
- Medicine's 'Basic' Mistake: How the Molecular Revolution Displaced an Entire Category of Inquiry.Journal of evaluation in clinical practice · 2026Review
- Neural regulation of tumor immunity: emerging opportunities to enhance cancer immunotherapy.Experimental & molecular medicine · 2026Review
- Regulation of immune checkpoint molecules in cancer immune evasion and therapy.Nature reviews. Cancer · 2026Review
- Depression remodels tumor microenvironment to drive tumor progression: Bio-behavioural signalling pathways and clinical interventions.Journal of advanced research · 2026Review
- Integrated Spatial Metabolomics and Transcriptomics Decipher the Effect of Chronic Stress on the Progression of Liver Cancer.Applied biochemistry and biotechnology · 2026Article
- Neuro-immune crosstalk in the tumor microenvironment: mechanisms and therapeutic implications for cancer immunotherapy.Journal of neuroinflammation · 2026Review
- β-Adrenergic receptors as immunomodulators in T cells: mechanisms of neuroimmune crosstalk and pathophysiological implications.Molecular medicine (Cambridge, Mass.) · 2026Review
- Impact of baseline medications on real-world overall survival in immune checkpoint inhibitor-treated patients with cancer in the RADIOHEAD cohort.Med (New York, N.Y.) · 2026Article
55 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Metabolic dysfunction and exhaustion in tumor-infiltrating T cells have been linked to ineffectual antitumor immunity and the failure of immune checkpoint inhibitor therapy. We report here that chronic stress plays a previously unrecognized role in regulating the state of T cells in the tumor microenvironment (TME). Using two mouse tumor models, we found that blocking chronic adrenergic stress signaling using the pan β-blocker propranolol or by using mice lacking the β2-adrenergic receptor (β2-AR) results in reduced tumor growth rates with significantly fewer tumor-infiltrating T cells that express markers of exhaustion, with a concomitant increase in progenitor exhausted T cells. We also report that blocking β-AR signaling in mice increases glycolysis and oxidative phosphorylation in tumor-infiltrating lymphocytes (TIL), which associated with increased expression of the costimulatory molecule CD28 and increased antitumor effector functions, including increased cytokine production. Using T cells from Nur77-GFP reporter mice to monitor T-cell activation, we observed that stress-induced β-AR signaling suppresses T-cell receptor (TCR) signaling. Together, these data suggest that chronic stress-induced adrenergic receptor signaling serves as a "checkpoint" of immune responses and contributes to immunosuppression in the TME by promoting T-cell metabolic dysfunction and exhaustion. These results also support the possibility that chronic stress, which unfortunately is increased in many patients with cancer following their diagnoses, could be exerting a major negative influence on the outcome of therapies that depend upon the status of TILs and support the use of strategies to reduce stress or β-AR signaling in combination with immunotherapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.